Diabetes, a major risk factor for development of periodontal disease, has increased in prevalence by 400% since 1980. Of the 25 million diabetic patients in the United States, it is estimated that 7.5 million have severe periodontitis. It is generally accepted that the severity of periodontal disease is correlated with the presence of inflammation. However, inflammation fails to completely explain the rapid progression of periodontal disease, generalized skeletal bone loss, and marrow fat accumulation that can be observed in young insulin-dependent diabetics with low plaque levels and good oral hygiene. Therefore, it is likely that other mechanisms are mediating the coupling of bone loss and diabetes. Since 1967 it has been repeatedly noted that clinical neuropathy is correlated with both the prevalence and severity of periodontal disease in diabetic patients. The skeleton and periodontal complex are highly innervated and local changes in nerve function have the capacity to regulate both the bone microenvironment and the overlying inflammatory response. However, despite significant correlative evidence linking neuropathy and periodontal disease in diabetes, the ability of local neuropathic change to contribute to bone loss, marrow fat accumulation and periodontal disease development in diabetes remains unexplored. Our central hypothesis is that in diabetes, sensory denervation and depletion of sensory neuropeptides in the skeleton enhances vasoconstriction and accumulation of marrow fat while limiting bone regeneration. These changes would predispose diabetic patients to development of osteopenia and progression of periodontal disease. If targeted neural dysfunction is identified as an underlying cause of bone loss and periodontal disease, treatment and prevention strategies will have the potential for significant evolution. We will test our hypothesis in rodent models of streptozotocin induced insulin-dependent diabetes with or without chemical, physical or transgenic inhibition of neural signaling. When this work is completed we expect to identify neural regulators of skeletal metabolism and determine the in vivo relevance of these findings to progression of diabetes-associated bone loss and periodontal disease. These outcomes are expected to have a broad positive impact because neural regulation of the skeleton is relevant to other conditions associated with bone loss and marrow fat accumulation including osteoporosis, aging, gonadal dysfunction and anorexia.